The present invention relates to alterations in the BRCA1 gene and methods for detecting such alterations.
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference, and for convenience are referenced in the following text by author and date and are listed alphabetically by author in the appended bibliography.
Breast cancer is the most common cancer in women and its impact on mortality and morbidity is significant and well documented (American Cancer Society, 1996). The etiology of breast cancer is related to hormonal, genetic, and environmental factors. From epidemiologic studies the increase in breast cancer risk associated with reproductive and other hormonal factors, diet, alcohol consumption and other environmental and host factors accounts for less than 50% of cases (Kelsey, 1993). Breast cancer affects one in eight women, and is their second leading cause of death from cancer (Boring et al., 1994), whereas ovarian cancer, although less frequent, is the leading cause of death from gynecologic malignancies in North America. It is estimated that 5-10% of breast cancer cases may be due to inherited autosomal dominant susceptibility genes (Claus et al., 1991; Hoskins et al., 1995). Ovarian cancer is also known to have a familial component (Schildkraut et al., 1988; Cannon-Albright, 1994).
Breast cancer occurs in hereditary and sporadic forms. Hereditary breast cancers are genetically heterologous. Susceptibility is variously attributable to germline mutations in the BRCA1 gene (Miki et al., 1994), BRCA2 gene (Wooster et al., 1995, Tavtigian et al., 1996), TP53 gene (Malkin et al., 1990) or ataxia telangiectasia gene (Savitsky et al., 1995), each of which is considered to be a tumor suppressor. Female BRCA1 mutation carriers are estimated to have an 87% lifetime risk of developing breast cancer and a 44% risk of ovarian cancer in breast/ovarian families (Easton et al., 1993; Steichen-Gersdorf et al., 1994; Narod et al., 1995; Easton et al., 1995; Ford et al., 1995; Ford et al., 1994). Moreover, BRCA1 carriers have a four-fold increased risk of colon cancer, whereas male carriers face a three-fold increased risk of prostate cancer (Ford et al., 1994). Mutations in the BRCA1 gene account for approximately 45% of familial breast cancer and 90% of inherited breast/ovarian cancer (Miki et al., 1994; Szabo and King, 1995). In addition, BRCA2 carriers have an increased risk of pancreatic cancer. Mutations in the BRCA2 gene account for a comparable percentage of inherited breast cancer cases (Wooster et al., 1995; Tavtigian et al., 1996). Over 85 distinct BRCA1 mutations and a growing list of BRCA2 mutations have been identified, with the majority resulting in protein truncation (The Breast Cancer Information Core). In addition, a wide array of polymorphic variants have been seen for both BRCA1 and BRCA2.
The BRCA1 gene contains 5592 bp of coding sequence encompassed within 23 exons spread over more than 70 kb of genomic DNA and encodes a protein of 1863 amino acids. The BRCA2 gene contains 10,443 bp of coding sequence encompassed within 27 exons spread over roughly 70 kb of genomic DNA and encodes a protein of 3418 amino acids.
Identification of the high risk of breast and ovarian cancer due to genetic defects in BRCA1 has led to an enormous effort to identify the spectrum of mutational lesions that occur in this gene. Thus, it is desired to identify additional alterations, including mutations and polymorphisms, which are present in the BRCA1 gene. Such alterations are useful in analysis of an individual's risk to develop breast and ovarian cancer as a result of such alterations.